Adolescence is a unique transitional time, long noted for emotional turmoil, increased vulnerability to addiction and the onset of psychiatric disorders such as depression and schizophrenia. The neural restructuring that occurs at this time may result in increased vulnerability to the environment including stress. The prefrontal cortex of humans, in particular, decreases in size during adolescence with different timing and slope of trajectories in each sex (Lenroot et al, 2007). This means that the cellular basis for the size decrease must also differ between males and females. Pruning of neurons, dendrites, synapses and receptors occurs in the prefrontal cortex during adolescence in humans and other species (Huttenlocher, 1979; Lewis, 1997; Andersen et al, 2000; Markham et al, 2007), and there are indications of sex differences in pruning in the rare instances where they have been examined. The timing of pruning will be investigated here in Aim 1, and the implications of sex differences in this timing will be tested with stress in Aim 2. Stress during human adolescence is a known predisposition for psychopathology and can precipitate symptoms (Grant et al, 2004; Arnsten, 2011) which indicates a disruption of normal pruning. There are sex differences in the behavioral reaction to stress in adolescents (Romeo; 2010; Wilkin et al, 2012). This may contribute to the incidence and severity of schizophrenia during adolescent onset (1.4:1 male>female) as well as in the lifetime occurrence of depressive disorders (2:1 female>male) (Abel et al, 2010; Parker & Brotchie, 2010). Thus sex and stress interact in the sculpting of potentially vulnerable circuits during adolescence. Our long-term goal is to understand how the neural changes during adolescence can go awry to precipitate psychopathologies in a sexually dimorphic pattern. The central hypothesis of the present proposal is that there are sex differences in the timing of pruning during adolescence that result in differential vulnerabilitiesto stress.